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Clinical science

The effect of hypercapnia on the sensitivity to flicker defined stimuli A M Shahidi,1 C Hudson,1,2 S R Patel,1 J G Flanagan1,2 1

Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada 2 School of Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada Correspondence to Professor John G Flanagan, Department of Ophthalmology and Vision Sciences, University Health Network, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8; jgfl[email protected] Received 20 December 2013 Revised 20 March 2014 Accepted 31 August 2014 Published Online First 17 September 2014

ABSTRACT Background/Aims To investigate the effect of increased CO2 levels on flicker defined stimuli. Methods The sensitivity of two flicker defined tasks was measured in nine healthy, trained observers using the Flicker Defined Form (FDF) stimulus of the Heidelberg Edge Perimeter (HEP; Heidelberg Engineering) and Frequency Doubling Technology (FDT) stimulus of the Matrix perimeter (Carl Zeiss Meditec) during normoxia and 15% hypercapnia (end-tidal CO2 increased by 15% relative to baseline). HEP-FDF and Matrix-FDT sensitivities were analysed for the global field, superior and inferior hemifields and at specific matched eccentricities, using repeated measures analysis of variance. The main effect of hypercapnia on flicker sensitivity was analysed using regression models. Results Higher flicker sensitivity outcomes with increasing CO2 values were found for HEP-FDF and Matrix-FDT with a statistically significant main effect for HEP-FDF global, superior and inferior hemifields ( p0.05). Conclusions As CO2 levels were increased in healthy young individuals, there was an associated increase in visual sensitivity that was only significant for HEP-FDF stimuli, highlighting the different mechanisms involved in processing each of HEP-FDF and Matrix-FDT stimuli. Mean visual sensitivity outcomes were found to be similar for normocapnia and hypercapnia suggesting that a capability to compensate for a mild and stable increase in systemic CO2 levels may exist. INTRODUCTION

To cite: Shahidi AM, Hudson C, Patel SR, et al. Br J Ophthalmol 2015;99: 323–328.

Hypercapnia is widely used as a vasodilatory stimulus in clinical and basic research to investigate the pathophysiology of vascular disease. Hypercapniainduced elevation in retinal and choroidal blood flow in healthy individuals suggests that metabolic autoregulatory mechanisms adapt to tissue CO2 levels.1 2 There is a growing body of evidence that significant changes in systemic blood flow are associated with visual functional challenges during different breathing gas concentrations. For example, a 2.5% increase in inhaled CO2 affects cellular activity from the retina to the visual cortex resulting in impaired coherent motion.3 Animal models have shown that the electroretinogram (ERG) b-wave amplitudes are decreased during hypercapnia compared with increased c-wave amplitudes, suggesting higher sensitivity of the neural retina, rather than

the retinal pigment epithelium.4 Additionally, decreased temporal contrast sensitivity in young healthy individuals in response to hypercapnia has been documented.5 When assessing such effects in disease, hypercapnia-induced vasodilatation in patients with normal tension glaucoma was reported to significantly improve the central visual function, but only in those who also had increased ocular pulse amplitudes.6 This outcome has been explained by the likelihood of compromised glaucomatous neurons responding to improved circulation caused by hypercapnia. There are also conflicting reports on the effect of other breathing gas conditions on visual function. For example, hypoxia was shown to degrade temporal contrast sensitivity as measured by frequency doubling technology (FDT)7 while another report showed similar static and flicker visual field sensitivity between mild hypoxic and normoxic conditions.8 Flicker defined form (FDF) is known to create a ‘phantom edge counter illusion’.9 10 It is a flicker defined, phase difference stimulus, that has been reported to be dependent on the fast-acting contour extraction system, dominated by the magnocellular system, but is still influenced by the slow surface system, a parvocellular mechanism.10 11 FDT perimetry, although named after the frequency doubling phenomenon, measures flicker contrast-detection thresholds.12 13 Both techniques claim to be sensitive to early functional loss in glaucoma.14–16 Although both are flicker defined stimuli, they differ in that FDF is a phase difference threshold task that is dependent on higher order processing. It uses principles similar to those found under conditions of divided attention.17 To perceive the FDF stimulus, that is a change in phase across a contour, the observer has to view a field of distracting flickering elements. However, the FDT stimulus is a relatively simple, single, counter phase flickering patch presented on an otherwise uniform background.12 The application of different gas delivery provocations has resulted in contradictory findings for various visual function outcomes. Our laboratory has previously shown that a 15% increase in end tidal CO2 can significantly increase haemodynamic parameters in normal healthy individuals.18 Additionally stimulation of the retina with flickering light can increase retinal blood flow potentially as a result of tight neurovascular coupling.19 20 The aim of the current research was to investigate the effect of stabilised systemic hypercapnia on the sensitivity to flicker defined stimuli of differing complexities. It was hypothesised that increased partial pressure of CO2 will significantly improve sensitivity to flicker defined stimuli.

Shahidi AM, et al. Br J Ophthalmol 2015;99:323–328. doi:10.1136/bjophthalmol-2013-304814

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Clinical science MATERIALS AND METHODS Participants This study was performed in adherence to the tenets of the Declaration of Helsinki and was approved by the Toronto Western Hospital Research Ethics Board and the University of Waterloo Research Ethics Board. Written informed consent was obtained from 9 healthy non-smoking individuals (6 male) aged between 21 years and 36 years (28.9±4.77 years). One eye was selected randomly for testing. All participants underwent an ophthalmic screening of visual acuity (visual acuity 0.87, p>0.12). The average PETCO2 increased significantly from baseline (35.8 ±4.1 mm Hg) to hypercapnia (41.2±4.8 mm Hg ( p=0.02) ie, an average increase of PET CO2 of 15%) when performing the HEP and Matrix ( p=0.02). Blood pressure was slightly higher during hypercapnia compared with baseline but not significantly (HEP(df 17, 1): 116/75±6.4 at baseline versus 120/77±4 at hypercapnia, p=0.194 systolic and p=0.315 for diastolic; Matrix(df 17, 1): 116/75±7 at baseline versus 120/76±6 at hypercapnia, p=0.17 for systolic and p=0.43 for diastolic). Heart rate remained unchanged when comparing baseline with the hypercapnia condition (76±10 at baseline versus 75±11 at hypercapnia for both instruments, p=0.609). No detectable changes in SpO2 were found from baseline to hypercapnia (98±1 for normocapnia and hypercapnia for both instruments, p=0.215).

Normocapnia-hypercapnia comparison Flicker stimuli Flicker defined form The 24-2 adaptive staircase threshold estimation algorithm was used to perform Heidelberg Edge Perimeter (HEP)-FDF using a HEP (Heidelberg Engineering, Heidelberg Engineering, 324

The within subject comparisons between the two gas provocations for the HEP-FDF showed no statistically significant differences in the global field, superior/inferior hemifields or by eccentricity ( p>0.16 for all comparisons). There were no within-subject differences also for the Matrix-FDT sensitivity

Shahidi AM, et al. Br J Ophthalmol 2015;99:323–328. doi:10.1136/bjophthalmol-2013-304814

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Clinical science Table 1 Data shown as Mean±SD, HEP-FDF data has been rescaled to match the Matrix-FDT data (HEP sensitivity×1.414) Sensitivity HEP-FDF Normocapnia Hypercapnia Mean sensitivity comparison† Effect of CO2 on sensitivity‡ 95% CI Matrix-FDT Normocapnia Hypercapnia Mean sensitivity comparison† Effect of CO2 on sensitivity‡ 95% CI

Global (dB)

Superior (dB)

Inferior (dB)

MD

PSD

26.49±2.26 26.27±2.67 F(8,1)=0.35 p=0.57 F(17,1)=8.01 p0.05 for all) (figure 3). MD and PSD values were also not found to be statistically associated with CO2 values ( p=0.23 and 0.17, respectively) (table 1).

DISCUSSION Association between hypercapnia and sensitivity As shown by the regression results, sensitivity to HEP-FDF stimuli was found to be significantly increased in all geographical Table 2

Data shown as Mean±SD, HEP-FDF data has been rescaled to match the Matrix-FDT data (HEP sensitivity×1.414)

Eccentricity HEP-FDF Normocapnia Hypercapnia Mean sensitivity comparison† Effect of CO2 on sensitivity‡ 95% CI Matrix-FDT Normocapnia Hypercapnia Mean sensitivity comparison† Effect of CO2 on sensitivity‡ 95% CI

This study aimed to explore whether mild and stable systemic hypercapnia had any influence on visual function as measured by two different flicker defined stimuli in healthy, trained



12°

18°

24°

27.96±2.02 27.29±2.52 F(8,1)=1.29 p=0.28 F(17,1)=4.64 p=0.04 0.06 to 0.51

27.73±2.55 27.62±3.31 F(8,1)=0.005 p=0.94 F(17,1)=4.34 p=0.05 0.14 to 0.46

26.77±3.03 26.87±2.82 F(8,1)=0.006 p=0.94 F(17,1)=5.66 p=0.03 0.15 to 0.57

24.31±2.86 24.43±2.68 F(8,1)=0.01 p=0.91 F(17,1)=7.20 p=0.01 0.12 to 0.51

31.19±2.72 30.33±3.57 F(8,1)=0.86 p=0.38 F(17,1)=1.42 p=0.25 –0.91 to 0.50

30.14±2.73 29.15±2.95 F(8,1)=0.09 p=0.09 F(17,1)=3.69 p=0.07 –1.26 to 1.03

27.86±2.80 27.08±2.64 F(8,1)=0.002 p=0.55 F(17,1)=2.15 p=0.16 –0.66 to 0.94

26.76±2.96 25.89±3.07 F(8,1)=0.23 p=0.23 F(17,1)=2.35 p=0.14 –0.71 to 0.90

†Repeated Measure ANOVA comparing average sensitivity between the two gas conditions. ‡Regression assessing general effect of CO2 on sensitivity to flicker-defined stimuli. ANOVA, analysis of variance; dB, decibel; FDF, Flicker Defined Form; FDT, Frequency Doubling Technology; HEP, Heidelberg Edge Perimeter.

Shahidi AM, et al. Br J Ophthalmol 2015;99:323–328. doi:10.1136/bjophthalmol-2013-304814

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Clinical science

Figure 1 Box plots demonstrating the comparisons between normocapnia and hypercapnia for Matrix-FDT eccentrically (top left) and geographically (top right) and for HEP-FDF eccentrically (bottom left) and geographically (bottom right). Note: HEP-FDF data are rescaled (HEP-FDF sensitivity×1.414) to match FDT data. FDF, Flicker Defined Form; FDT, Frequency Doubling Technology; HEP, Heidelberg Edge Perimeter.

observers. Albeit no significant differences were found in mean sensitivity values between normocapnia and hypercapnia, our regression results suggest an increase in sensitivity as shown by the HEP-FDF outcomes (MD, superior, inferior, global as well as eccentricity values) with increased levels of CO2. The fact that this association was found with MD but not PSD indicates that the change is global rather than localised.

Figure 2 Mean sensitivity differences between hypercapnia and normocapnia breathing levels at different eccentricities of the visual field. The bars indicate SE of the mean. FDF, Flicker Defined Form; FDT, Frequency Doubling Technology; HEP, Heidelberg Edge Perimeter. 326

The significant effect of CO2 on visual function, in this case sensitivity to HEP-FDF stimuli, is in agreement with some previous research. Huber et al23 reported that hypercapnia improved contrast sensitivity, possibly as a result of increased blood flow and blood oxygen levels. More recently, it has been shown that changes in retinal and choroidal blood flow as a result of hypercapnia or hypocapnia significantly improved or reduced visual acuity, respectively, with a significant correlation with increased arterial blood flow during hypercapnia.24 Finally, Hosking et al25 reported lower contrast sensitivity during hypercapnia in patients with untreated glaucoma compared with controls, possibly caused by an impaired circulation. These findings suggest that improved ocular blood flow has a significant positive effect on visual function. It is also well established that mild hypercapnia increases peripheral perfusion and tissue PO2 as a result of central chemoreceptor response which in turn increases the cardiac output26 and/or by locally mediating peripheral vasodilation, which in turn overcomes sympathetic vasoconstriction.27 Consequently, an increase in blood CO2 levels has been known to trigger the dissociation of oxyhaemoglobin and thus increase haemoglobin O2 loading (Bohr effect), which can potentially contribute to changes in ocular blood flow and ultimately visual function. The method of gas delivery used in this study minimised alterations in systemic PO2 concentrations resulting in tight, and stable, control of O2 and CO2 end-tidal levels. Our laboratory has

Shahidi AM, et al. Br J Ophthalmol 2015;99:323–328. doi:10.1136/bjophthalmol-2013-304814

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Clinical science

Figure 3 Top: Matrix-FDT sensitivity in the global field, superior and inferior hemifields (left), and eccentrically (right) showed a non-significant trend towards increasing in association with increased PETCO2. Bottom: HEP-FDF sensitivity significantly increased in global field, superior and inferior hemifields (left), and eccentrically (right) in association with increased PETCO2. Note: HEP-FDF data are rescaled (HEP-FDF sensitivity×1.414) to match the FDT data. FDF, Flicker Defined Form; FDT, Frequency Doubling Technology; HEP, Heidelberg Edge Perimeter.

previously shown that retinal vascular reactivity responses to various gas provocations can be isolated using this system as it is capable of stabilising end-tidal O2 and CO2 during hyperoxic and hypercapnic provocations.28 Hence, the increase in sensitivity to flickering stimuli could potentially be attributed to a response to mild hypercapnia. Based on the regression models, it was found that HEP-FDF and Matrix-FDT sensitivities were higher for those who had higher PETCO2 values at baseline. When the overall effect of increasing CO2 was assessed HEP-FDF showed statistically significant associations with changes in CO2. The two stimuli are somewhat different in spite of both being flicker-defined. FDF is generated using a phase difference, and is influenced by the complexities of divided attention as there are flickering random dots over the entire field.17 FDT is a simple flicker contrast threshold stimulus, generated by a patch of counter-phase flickering gratings against an uniform background.12 An important concern in such studies is whether findings could be due to a possible learning effect. All participants in the present study were familiar with the breathing and flicker test procedures. Additionally, learning effect was controlled for by randomising the order of the flicker tests. It should be noted that the current results for sensitivity to flicker-defined stimuli showed greater reduction at further eccentricities under both gas conditions and with both methods. Previous work on the effect of hypoxia and hypocapnia on Matrix-FDT also showed that sensitivity paracentral from the fovea was degraded, specifically with hypoxia.7 In this study we observed similar reduction trends for HEP-FDF and Matrix-FDT under both breathing conditions. Additional post hoc analyses showed no significant difference by eccentricity ( p

The effect of hypercapnia on the sensitivity to flicker defined stimuli.

To investigate the effect of increased CO2 levels on flicker defined stimuli...
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